Question 1

A 33-year-old female patient presented complaining of a tender abdomen and fever. Examination revealed marked abdominal distension, acidosis, and leukocytosis. Laparoscopy revealed that large parts of the small intestine were necrotic and as a consequence, the entire ileum and the proximal portion of her colon were resected. Due to the resulting loss of a particular set of enteroendocrine cells, this patient is most likely to experience which of the following?

Accepted Answer

The patient has lost the ileum, which is the primary site of production of cholecystokinin (CCK). CCK is a hormone that stimulates the release of pancreatic enzymes and bile, and also inhibits gastric emptying. Loss of CCK will therefore lead to decreased pancreatic enzyme and bile secretion, and increased gastric emptying.  PYY is produced by, and secreted from, intestinal enteroendocrine L-cells of the ileum and colon. Within the gastrointestinal tract, the highest detectable levels of PYY are found in the rectum with low levels found in the duodenum and jejunum. Within the central nervous system (CNS), PYY is detectable in the hypothalamus, medulla, pons, and spinal cord. The signals associated with the response of the proximal gut to food intake that lead to PYY release are the result of CCK and gastrin activity.

Question 2

A 14-year-old boy presents with weight loss and diarrhea. His tongue becomes sore and blistery after eating oatmeal or rye bread, which leads to the diagnosis of celiac disease. The boy and his parents are advised to be sensitive to symptoms of malabsorption of calcium. Which of the following would be a most likely symptom of which the parents should be aware?

Accepted Answer

Calcium malabsorption in celiac disease can lead to hypocalcemia, which may cause muscle tetany. In patients with celiac disease, the protein gluten, which is found in bread, oats, and many other foods containing wheat, barley, or rye, triggers an autoimmune response that causes damage to the small intestine, leading to widespread manifestations of malabsorption. Calcium is difficult to absorb, so patients frequently experience symptoms of hypocalcemia such as muscle cramping, tetanic contractions, numbness, and tingling sensations. For sensory and motor nerves, calcium is a critical second messenger involved in normal cell function, neural transmission, and cell membrane stability. The nerves respond to a lack of calcium with hyperexcitability.

Question 3

As a physician on a mission to treat patients in subSaharan Africa you encounter numerous children with a common cluster of signs and symptoms. These include chronic diarrhea, dizziness, fatigue, delayed wound healing, and muscle wasting. Given the constellation of symptoms in your patients, you make a diagnosis of marasmus. Which of the following is the principal cause of the observed symptoms?

Accepted Answer

Marasmus is caused by a severe deficiency in total caloric intake, including protein, carbohydrates, and fats, leading to symptoms like muscle wasting and delayed wound healing. The children you are treating are suffering from marasmus. Marasmus is a form of severe malnutrition caused by a deficiency of nearly all nutrients, especially protein and carbohydrates. A typical child with marasmus looks emaciated and has a body weight less than 60% of that expected for the age. Treatment of marasmus is normally divided into 2 phases. The initial acute phase of treatment involves restoring electrolyte balance, treating infections, and reversing the hypoglycemia and hypothermia. This is followed by refeeding and ensuring that sufficient caloric and nutrient intake is maintained to enable catch-up growth in order to restore a healthy normal body mass.

Question 4

You are treating a 12-year-old male patient exhibiting severe episodes of hypoglycemia. Measurement of circulating insulin and glucagon levels indicate that they are normal and responsive to cycles of feeding and fasting. The hypoglycemia can most easily be explained as a defect in which of the following processes?

Accepted Answer

Hepatic gluconeogenesis is crucial for maintaining blood glucose levels during fasting. A defect in this process can lead to hypoglycemia despite normal insulin and glucagon levels. The hepatic form of hexokinase (glucokinase), in this patient, most likely harbors a mutation that results in a significantly reduced K_m relative to normal glucokinase. Hepatic glucokinase normally has a K_m significantly higher than that of the hexokinase that is expressed in other insulin-responsive tissues such as adipose tissue and skeletal muscle. This prevents the liver from trapping glucose, thereby ensuring that peripheral tissues such as the brain and muscle have easy access to dietary carbohydrate. In the case of this patient, the expression of a variant glucokinase with a K_m similar to that of muscle hexokinase would result in significant trapping of glucose inside hepatocytes. The outcome would be expected to be periods of hypoglycemia as observed in this patient.

Question 5

A healthy 35-year-old man exhibits a peak serum glucose concentration of 215 mg/dL within 30 minutes of participating in a glucose tolerance test involving the consumption of 60 g of glucose. Two hours after ingestion, measurement of his serum glucose concentration shows it to be to 85 mg/dL. The observed decrease is due to the normal responses of tissues to insulin. In addition, part of the reduction is due to uptake and trapping of glucose within the liver cells, which is facilitated by which of the following enzymes?

Accepted Answer

Glucokinase is the enzyme that facilitates the uptake and trapping of glucose within liver cells by phosphorylating glucose to glucose-6-phosphate, which is a crucial step in glucose metabolism. Hepatic glucokinase has a high K_m for glucose in order to ensure that the liver does not trap glucose before sufficient levels are obtained in the blood. This allows dietary carbohydrate to pass through the liver so that tissues such as the brain, skeletal muscle, erythrocytes, and kidney medulla can have access to the glucose. As the level of blood glucose increases, glucokinase will become more active, resulting in phosphorylation of more glucose thereby, trapping it in the hepatocyte.

Question 6

A 9-month-old child is presented to the emergency room by his parents who report that he has been vomiting and has severe diarrhea. The episodes of vomiting began when the mother stopped breastfeeding and switched to the use of child cow's milk. The infant exhibits signs of failure to thrive, weight loss, hepatomegaly, and jaundice. Laboratory tests show elevated blood galactose, hypergalactosuria, and metabolic acidosis with coagulation deficiency characteristic of classic galactosemia. Which of the following is most likely to occur if this child continues to consume cow's milk?

Accepted Answer

Type 1 galactosemia occurs as a consequence of mutations in the gene encoding GALT. Classic galactosemia manifests by a failure of neonates to thrive. Vomiting and diarrhea occur following ingestion of milk, hence individuals are termed lactose intolerant. Clinical findings include impaired liver function (which if left untreated leads to severe cirrhosis), elevated blood galactose, hypergalactosemia, hyperchloremic metabolic acidosis, urinary galactitol excretion, and hyperaminoaciduria. Unless controlled by exclusion of galactose from the diet, these patients can go on to develop blindness and fatal liver damage. Blindness is due to the conversion of circulating galactose to the sugar alcohol galacitol, by an NADPH-dependent aldose reductase that is present in neural tissue and in the lens of the eye.

Question 7

Prolonged ethanol consumption and subsequent metabolism ultimately leads to a condition referred to as steatohepatitis or more commonly, "fatty liver syndrome." The increased fat deposition in hepatocytes in response to chronic alcohol consumption is the result of which of the following?

Accepted Answer

Chronic alcohol consumption increases the activity of glycerol-3-phosphate dehydrogenase, leading to an increase in glycerol-3-phosphate, which is a substrate for triglyceride synthesis, contributing to fat accumulation in the liver.  The metabolism of ethanol by the liver leads to a large increase in NADH. This increase in NADH disrupts the normal processes of metabolic regulation such as hepatic gluconeogenesis, TCA cycle function, and fatty acid oxidation. Concomitant with reduced fatty acid oxidation is enhanced fatty acid synthesis and increased triacylglycerol production by the liver. In the mitochondria, the production of acetate from acetaldehyde leads to increased levels of acetyl-CoA. Since the increased generation of NADH also reduces the activity of the TCA cycle, the acetyl-CoA is diverted to fatty acid synthesis. The reduction in cytosolic NAD+ leads to reduced activity of glycerol-3-phosphate dehydrogenase (in the glycerol 3-phosphate to DHAP direction), resulting in increased levels of glycerol 3-phosphate, which is the backbone for the synthesis of the triglycerides. Both of these 2 events lead to fatty acid deposition in the liver, leading to fatty liver syndrome and excessive levels of lipids in the blood, referred to as hyperlipidemia.

Question 8

Shortly after birth, an infant presents with severe lactic acidemia, hyperammonemia, citrullinemia, and hyperlysinemia with the presence of a-ketoglurate in the urine. Tests are performed to determine where the defect lies that is causing this cluster of symptoms. These tests indicate that the infant does not have a urea cycle defect, nor a defect in fatty acid oxidation. A defect in which of the following metabolic pathways is most likely the cause of this infants symptoms?

Accepted Answer

The infant is experiencing symptoms associated with a defect in pyruvate carboxylase. Pyruvate carboxylase is the first enzyme in the gluconeogenic conversion of pyruvate carbons into glucose. A defect in pyruvate carboxylase would restrict the conversion of lactate into pyruvate and then subsequently to glucose. This would lead to severe lactic academia. The other symptoms are primarily the result of liver damage due to impaired gluconeogenesis.

Question 9

Which of the following statements concerning total body energy storage is correct?

Accepted Answer

Most of the body's energy store is held as lipid, primarily in the form of triglycerides in adipose tissue. Lipid is the most concentrated form of energy storage, holding 9.4 kcal/g. For a typical 70-kg human, over 130,000 kcal is typically stored as fat. Storage of energy as available protein is about 20,000 kcal while storage as carbohydrate is about 3000 kcal.

Question 10

During early fasting, glycogen is used as a source of glucose for the blood. After liver glycogen is depleted, which of the following is most likely to contribute to the maintenance of endogenous serum glucose levels?

Accepted Answer

Intestinal glutamine is used as a gluconeogenic substrate. During periods of fasting and starvation, when liver glycogen levels are depleted, the major source of carbon atom for hepatic gluconeogenesis is from the amino acids released due to protein degradation within skeletal muscle. However, the kidneys and the small intestine do contribute to endogenous glucose production via the use of glutamine as a carbon source for gluconeogenesis in these 2 tissues.

Question 11

You are treating a patient who is suffering from the glycogen storage disease known as von Gierke disease. Although the primary defect in this disease is in glucose homeostasis, which of the following other metabolic abnormalities is expected to be found in patients with this disease?

Accepted Answer

Von Gierke disease is characterized by a deficiency in glucose-6-phosphatase, leading to impaired gluconeogenesis and glycogenolysis. This results in the accumulation of glucose-6-phosphate, which is shunted into the pentose phosphate pathway, increasing ribose-5-phosphate and subsequently purine synthesis. The excess purines are degraded to uric acid, leading to hyperuricemia. The metabolic consequences of the hepatic glucose-6-phosphate deficiency of von Gierke disease extend well beyond just the obvious hypoglycemia that results from the deficiency in liver in being able to deliver free glucose to the blood. The inability to release the phosphate from glucose 6-phopsphate results in diversion into glycolysis and production of pyruvate as well as increased diversion onto the pentose phosphate pathway. The production of excess pyruvate, at levels above the capacity of the TCA cycle to completely oxidize it, results in its reduction to lactate leading to lactic acidemia. In addition, some of the pyruvate is transaminated to alanine, leading to hyperalaninemia. Some of the pyruvate will be oxidized to acetyl-CoA, which cannot be fully oxidized in the TCA cycle. So the acetyl-CoA will end up in cytosol, where it will serve as a substrate for triglyceride and cholesterol synthesis resulting in hyperlipidemia. The oxidation of glucose 6-phophate via the pentose phosphate pathway leads to increased production of ribose-5-phosphate, which then activates the de novo synthesis of the purine nucleotides. In excess of the need, these purine nucleotides will ultimately be catabolized to uric acid, resulting in hyperuricemia and consequent symptoms of gout

Question 12

Following a minor respiratory illness, a seemingly healthy, developmentally normal 15-month-old girl exhibited repeated episodes of severe lethargy and vomiting in the middle of the night. The parents brought the infant to the ER following a seizure. The child was hypoglycemic and was administered 10% dextrose, but remained lethargic. Blood ammonia was high, liver enzymes were slightly elevated, and urine ketones were only barely detectable. A diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is made. Measurement of which of the following would also be expected in this infant given the current diagnosis?

Accepted Answer

In MCAD deficiency, there is impaired fatty acid oxidation, leading to the accumulation of medium-chain dicarboxylic acids in the blood. Deficiency in MCAD is the most common inherited defect in the pathways of mitochondrial fatty acid oxidation. The most common presentation of infants with this disorder is episodic hypoketotic hypoglycemia following periods of fasting. Although the first episode may be fatal, and incorrectly ascribed to sudden infant death syndrome, patients with MCAD deficiency are normal between episodes and are treated by avoidance of fasting and treatment of acute episodes with intravenous glucose. Accumulation of acylcarnitines (dicarboxylic acids), in particular octanoylcarnitine, is diagnostic.

Question 13

A 7-year-old boy is examined by his pediatrician because of complaints of severe cramping pain in his legs whenever he rides his bike. In addition, he experiences nausea and vomiting during these attacks. The child has noted that the severity of the cramps is most intense after dinners that include baked potatoes or pasta and sometimes bread. Clinical studies undertaken following a treadmill test demonstrate myoglobinuria and hyperuricemia. Given these symptoms, it seems clear that the boy is suffering from Tarui disease. With which of the following symptoms would this disease also be expected to be associated?

Accepted Answer

Tarui disease (GSD7) is a glycogen storage disease, resulting from mutations in the gene encoding muscle and erythrocyte PFK1. The symptoms of this disease are very similar to those observed in patients suffering from McArdle disease (GSDV), in particular the presentation of exercise-induced pain and myoglobinuria. However, since Tarui disease also involves a defect in erythrocyte PFK1, there are associated mild forms of jaundice, resulting from accelerated destruction of erythrocytes.

Question 14

A 6-month-old who is failing to thrive is brought to your clinic. Tests reveal hepatosplenomegaly, muscle weakness and atrophy, hypotonia, and decreased deep tendon reflexes. Biopsy of the liver reveals initial stages of cirrhosis due to the accumulation of an abnormal glycogen whose structure resembles amylopectin. These results indicate the child is suffering from Andersen disease. Which of the following would also be expected in this child?

Accepted Answer

Andersen disease or glycogen storage disease type IV (GSDIV) is also known as amylopectinosis. The disease results from defects in the gene encoding glycogen branching enzyme, also called amylo-(1,4 to 1,6) transglycosylase. The disease manifests with progressive hepatosplenomegaly along with the storage of an abnormal glycogen that exhibits poor solubility in the liver. The abnormal glycogen is characterized by few branch points with long outer chains containing more a-1,4-linked glucose than normal glycogen. Due to this structure of glycogen, the presence of normal activities of glycogen phosphorylase and glucose 6-phosphatase, patients with Andersen disease manifest the above symptoms but in the presence of normal serum glucose regulation.

Question 15

A 4-month-old white male infant with a temperature of 38.4°C is examined by his pediatrician. His mother indicates that he has had the fever for the past 4 days, been listless, vomiting, and has watery stools. Blood work indicates the infants' blood pH is slightly acidic and shows reduced bicarbonate. Other untoward blood chemistry includes elevated liver enzymes. The child has a protuberant abdomen, thin extremities, and a doll-like face indicative of von Gierke disease. Given this diagnosis, what other deleterious symptom would be expected in this infant?

Accepted Answer

Von Gierke disease (Glycogen storage disease type I) is characterized by severe hypoglycemia due to the inability to convert glycogen to glucose, leading to low blood sugar levels.  von Gierke disease (GSDI) results from the absence of glucose-6-phosphatase activity. Patients with von Gierke disease can present during the neonatal period with lactic acidosis and hypoglycemia. The hallmark features of this disease are severe hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. The severity of the hypoglycemia and lactic acidosis can be such that in the past affected individuals died in infancy. Infants often have a doll-like facial appearance due to excess adipose tissue in the cheeks. The metabolic consequences of the hepatic glucose-6-phosphate deficiency of von Gierke disease extend well beyond just the obvious hypoglycemia that results from the deficiency in liver being able to deliver free glucose to the blood. The inability to release the phosphate from glucose 6-phopsphate results in diversion into glycolysis and production of pyruvate as well as increased diversion onto the pentose phosphate pathway. The production of excess pyruvate, at levels above the capacity of the TCA cycle to completely oxidize it, results in its reduction to lactate, leading to lactic acidemia. In addition, some of the pyruvate is transaminated to alanine, leading to hyperalaninemia. Some of the pyruvate, which cannot be fully oxidized in the TCA cycle, will be oxidized to acetyl-CoA and so the acetyl-CoA will end up in the cytosol, where it will serve as a substrate for triglyceride and cholesterol synthesis resulting in hyperlipidemia. The oxidation of glucose 6-phophate via the pentose phosphate pathway leads to increased production of ribose 5-phosphate, which then activates the de novo synthesis of the purine nucleotides. In excess of the need, these purine nucleotides will ultimately be catabolized to uric acid, resulting in hyperuricemia and consequent symptoms of gout.

Question 16

You are studying fatty acid synthesis in a cell line isolated from a hepatic cancer patient. You discover that addition of glucose 6-phosphate does not lead to an increase in the rate of palmitic acid synthesis as is the situation for normal hepatic cells. This indicates there is a defect in the allosteric regulation of fatty acid synthase (FAS). Which of the following would most likely also be observed in these cells?

Accepted Answer

Regulation of de novo fatty acid synthesis by phosphorylated sugars takes place via allosteric activation of the activity of FAS. Addition of glucose 6-phosphate (G6P) to cells would also result in changes in the level of allosteric regulation of phosphorylase and glycogen synthase. G6P is an allosteric inhibitor of phosphorylase and an activator of glycogen synthase, the net result therefore, would be an increased ability to store glycogen.

Question 17

The Randle hypothesis was proposed to explain the correlation between carbohydrate and lipid metabolic homeostasis and the effect of disruptions in both processes on diabetes and obesity. Which of the following statements best reflects the basis of the Randle hypothesis?

Accepted Answer

The Randle hypothesis, also known as the glucose-fatty acid cycle, suggests that increased levels of circulating free fatty acids can impair glucose uptake in skeletal muscle by inhibiting insulin action, which is a key factor in the development of insulin resistance.  The Randle hypothesis states that elevations in circulating free fatty acids (FFAs) interfere with insulin action in liver and skeletal muscle. Increased FFA uptake and metabolism by the liver results in an increased production of acetyl-CoA. All of the acetyl-CoA cannot be oxidized completely in the TCA cycle. The elevated acetyl-CoA levels result in inhibition of the PDHc, resulting in increased citrate transport to the cytosol. Increased cytosolic citrate inhibits PFK1, resulting in reduced glucose oxidation and an increase in glucose-6-phosphate levels. Increases in glucose-6-phosphate lead to inhibition of skeletal muscle hexokinase, resulting in reduced glucose utilization. In addition, the elevated plasma FFAs impair insulin receptor tyrosine phosphorylation of IRS1, leading to defects in insulin-mediated signaling events in target cells, primarily skeletal muscle. Loss of insulin signaling in skeletal muscle prevents glucose transporter (GLUT4) mobilization to the cell surface with a resultant block to glucose uptake. The overall consequences of a high-fat diet are a progressive impairment in hepatic glucose homeostasis, impairment of insulin-mediated glucose uptake by skeletal muscle, and pancreatic β-cell decompensation. The latter leads to reduced insulin secretion and, thus, further impairment of the role of insulin in regulation of blood glucose.

Question 18

You are treating 46-year-old man who has suffered a heart attack. Measurement of his serum cholesterol level indicates it is 500 mg/dL. His father died at 37 years of age from a massive heart attack, and one of his 2 younger siblings also has an increased serum concentration of total cholesterol. This patient most likely has a defect in LDL receptor function associated with familial hypercholesterolemia (FH). Which of the following additional signs is characteristic in patients with FH?

Accepted Answer

Arcus cornea is a common sign in patients with familial hypercholesterolemia due to the accumulation of cholesterol in the cornea.  The clinical characteristics of FH include elevated concentrations of plasma LDL and deposition of LDL-cholesterol in the arteries, tendons, and skin. Fat deposits in the arteries are called atheromas and in the skin and tendons they are called xanthomas. Xanthomas and the characteristic arcus cornea (whitish ring on the peripheral cornea) begin to appear in the second decade in heterozygotes, but will appear in childhood in homozygotes.

Question 19

You are treating a 38-year-old man whose chief complaint is occasional right upper quadrant pain. Analysis of blood samples shows elevated aspartate transaminase (AST) and alanine transaminase (ALT). History indicates that these same enzymes have shown elevated levels each of the past 3 years during routine blood work in conjunction with his annual physical examination. His history also indicates reflux esophagitis, hypertension, and hyperlipidemia. You order tests for serologic and biochemical markers for viral hepatitis and autoimmune liver disease and other metabolic liver diseases, but these results are negative. The patient has gained 50 lb since the age of 18. He consumes less than 5 standard alcoholic drinks per week. Which of the following is the most likely diagnosis in this case?

Accepted Answer

The patient's elevated liver enzymes, history of weight gain, and minimal alcohol consumption suggest nonalcoholic fatty liver disease (NAFLD), which is common in individuals with obesity and metabolic syndrome.  Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world. NAFLD is characterized by fatty infiltration of the liver in the absence of alcohol consumption. One of the most significant contributing factors to the development of NAFLD is insulin resistance in the liver. Additional pathophysiology includes an enhanced state of hepatic oxidative stress and lipid peroxidation, decreased antioxidant defenses, early mitochondrial dysfunction, and iron accumulation.

Question 20

A 59-year-old male is found unconscious in an alley and rushed to the emergency room (ER). He is disheveled, clad in dirty torn clothing, has filthy hair, and smells of urine and decaying trash. Emanating from the patient is a strong odor of alcohol. From information contained in his wallet, family are contacted and a history reveals that the man has been living on the streets for several years and that he suffers from severe post-traumatic stress disorder (PTSD). Upon entry into the ER he was administered an iv drip of 5% dextrose. Unfortunately the patient never regained consciousness and died within hours of admission to the hospital. Given the patient's condition and history, which of the following was the most likely cause of his death?

Accepted Answer

The administration of 5% dextrose without thiamine in a malnourished alcoholic can lead to Wernicke's encephalopathy, which can cause severe lactic acidosis and result in death. Chronic alcoholics have a tendency to very poor dietetic habits particularly those who are homeless or choose to live on the streets. The chronic poor nutritional intake in these individuals usually leads to severe vitamin deficiencies, in particular thiamine deficiency. Lack of adequate thiamine, especially in alcoholics, leads to Wernicke-Korsakoff syndrome, WKS. WKS is associated with significant deficit in the activity of dehydrogenases that require thiamine pyrophosphate (TPP) as a cofactor such as pyruvate dehydrogenase (PDH). In these individuals the capacity to carry out gluconeogenesis is severely impaired due primarily to excess alcohol metabolism and the resultant negative effects on liver function. Giving a person in this state an iv bolus of glucose (5% dextrose) results in massive increases in lactate production due to the lack of PDH activity. This increases an already lactic acidotic state to a potentially lethal acidosis.

Quiz 34: Nitrogen: Metabolic Integration

Prolonged ethanol consumption and subsequent metabolism ultimately leads to a condition referred to as steatohepatitis or more commonly, "fatty liver syndrome." The increased fat deposition in hepatocytes in response to chronic alcohol consumption is the result of which of the following?

Which of the following statements concerning total body energy storage is correct?

During early fasting, glycogen is used as a source of glucose for the blood. After liver glycogen is depleted, which of the following is most likely to contribute to the maintenance of endogenous serum glucose levels?

You are treating a patient who is suffering from the glycogen storage disease known as von Gierke disease. Although the primary defect in this disease is in glucose homeostasis, which of the following other metabolic abnormalities is expected to be found in patients with this disease?

The Randle hypothesis was proposed to explain the correlation between carbohydrate and lipid metabolic homeostasis and the effect of disruptions in both processes on diabetes and obesity. Which of the following statements best reflects the basis of the Randle hypothesis?